The cardiac glycosides and the sympathomimetic amines are the principal inotropic agents used in the management of congestive heart failure. Although the cardiac glycosides, especially digitalis, are among the most frequently prescribed drugs, they have numerous liabilities such as a low therapeutic index and erratic absorption, and are associated with life-threatening arrhythmias and deleterious drug-drug interactions. In addition, many patients either do not respond, or become refractory to these agents. The sympathomimetic amines, such as dopamine and epinephrine, have limited utility due to positive chronotropic effects, arrhythmogenic properties, and oral ineffectiveness.
More recently, new classes of inotropic agents have been found. Among these, certain 2-phenylimidazo[4,5-b]pyridines (U.S. Pat. Nos. 3,985,891 and 4,327,100) have been shown to possess inotropic and anticoagulant activity. U.S. Pat. Nos. 4,299,834 and 4,353,909, and German Patent DE No. 3,044,497, described in Derwent E/26 52573, describe similarly substituted purine and 6-hydroxy-imidazo[4,5-b]pyridine derivatives.
Imidazo[1,2-a]pyridines substituted at the 2-position with carbostyril derivatives are described in European Patent Application No. 52,016. The compounds are said to be useful as cardiotonic agents. The circulatory and respiratory effects of 2-(2-pyridyl)-[1,2,4]-triazolo[1,5-a]pyridine is described in Derwent Abstract D/39 70803 (abstracting Japanese Patent J5 6100783).
The present invention provides for a series of phenylimidazole compounds, their formulations, and their use as orally effective positive inotropic agents which have minimal effects on blood pressure and heart rate. The compounds also possess vasodilitation activity.